Antitumoral effects of dovitinib in triple-negative breast cancer are synergized by calcitriol in vivo and in vitro. Issue 214 (November 2021)

• Record Type: Journal Article
• Authors: García-Quiroz, Janice; Cárdenas-Ochoa, Nohemí; García-Becerra, Rocío; Morales-Guadarrama, Gabriela; Méndez-Pérez, Edgar A.; Santos-Cuevas, Clara; Ramírez-Nava, Gerardo J.; Segovia-Mendoza, Mariana; Prado-García, Heriberto; Avila, Euclides; Larrea, Fernando; Díaz, Lorenza
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 214(2021)
• Publication Date: 2021-11
• Subjects: TNBC Triple-negative breast cancer -- HER-2 human epidermal growth factor receptor 2 -- RTK receptor tyrosine kinase -- RTKI receptor tyrosine kinase inhibitor -- FGF fibroblast growth factor -- FGFR fibroblast growth factor receptor -- VEGF vascular endothelial growth factor -- VEGFR vascular endothelial growth factor receptor -- PDGFR platelet derived growth factor receptor -- VDR vitamin D receptor -- MBCDF-T MBCDF-Tum -- DRI dose-reduction index -- SPECT/CT single–photon emission computed tomography and radiographic computed tomography -- IC Inhibitory concentrations -- 99mTc-RGD2 99mTc-Ethylenediamine-N, N-diacetic acid/hydrazinonicotinamyl-Glu[cyclo(Arg-Gly-Asp-D-Phe-Lys)]2; Breast cancer -- Dovitinib -- Calcitriol -- Combination index -- Dose-reduction index -- Synergism; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2021.105979
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Calcitriol synergized dovitinib anticancer effects in vitro and in vivo. Calcitriol allowed for dovitinib dose-reduction in triple negative breast cancer. At clinically safe concentrations calcitriol + dovitinib are synergic to inhibit TNBC. Abstract: Chemotherapy is a standard therapeutic option for triple-negative breast cancer (TNBC); however, its effectiveness is often compromised by drug-related toxicity and resistance development. Herein, we aimed to evaluate whether an improved antineoplastic effect could be achieved in vitro and in vivo in TNBC by combining dovitinib, a multi-kinase inhibitor, with calcitriol, a natural anticancer hormone. In vitro, cell proliferation and cell-cycle distribution were studied by sulforhodamine B-assays and flow cytometry. In vivo, dovitinib/calcitriol effects on tumor growth, angiogenesis, and endothelium activation were evaluated in xenografted mice by caliper measures, Itgb3/VEGFR2-immunohistochemistry and 99m Tc-Ethylenediamine-N, N-diacetic acid/hydrazinonicotinamyl-Glu[cyclo(Arg-Gly-Asp-D-Phe-Lys)]2 ( 99m Tc-RGD2 )-tumor uptake. The drug combination elicited a synergistically improved antiproliferative effect in TNBC-derived cells, which allowed a 7-fold and a 3.3-fold dovitinib dose-reduction in MBCDF-Tum and HCC-1806 cells, respectively. Mechanistically, the co-treatment induced a cell cycle profile suggestive of cell death and DNA damage (accumulation of cells in SubG1, S, and G2/M phases), increased the number of multinucleated cells and inhibited tumor growth to a greater extent than each compound alone. Tumor uptake of 99m Tc-RGD2 was reduced by dovitinib, suggesting angiogenesis inhibition, which was corroborated by decreased endothelial cell growth, tumor-vessel density and VEGFR2 expression. In summary, calcitriol synergized dovitinib anticancer effects in vitro and in vivo, allowing for a significant dose-reduction of dovitinib while maintaining its antiproliferative potency. Our results suggest the beneficial convergence of independent antitumor mechanisms of dovitinib and calcitriol to inhibit TNBC-tumor growth.